JPH0641440B2 - Process for producing trans-β-benzoyl acrylate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention has the general formula (II) (In the formula, R represents an alkyl group or an aralkyl group), a method for producing a trans-β-benzoyl acrylic acid ester, which industrially advantageously produces the compound, which is important as an intermediate raw material for pharmaceuticals, fragrances, and the like. The purpose is to

(Prior Art) Conventionally, the most general ester synthesis method includes a dehydration reaction from a carboxylic acid and an alcohol. Examples of applying this ester synthesis method to β-benzoyl acrylate ester synthesis include, for example, There is a synthesis of ethyl β-benzoyl acrylate. In the dehydration reaction from β-benzoylacrylic acid and ethanol, β
-There is a report that ethyl benzoyl acrylate can be obtained, but there is no description about the geometrical isomerism of the raw material and the product, that is, cis and trans, and the specific implementation method is not disclosed [Nikkei, 88 , 224 (1967)]. On the other hand, in another report, the product obtained by the ethyl esterification reaction of β-benzoylacrylic acid with ethanol is
Refining is very difficult [Journal of the American Chemical Society (J.Amer.Chem.Soc.), 45 ,
222 (1923)] or a report that ethyl β-benzoyl-α-ethoxypropionate was obtained by a normal ethyl esterification reaction [Bretin of the Chemical
Society of Japan (Bull.Chem.Soc.Japan),
42 , 1353 (1969)], and β-benzoylacrylic acid and β-
Regarding the method for synthesizing benzoyl acrylic acid ester, there are many unclear points such as the behavior of the geometric isomers of the product, as well as the product and the quantitative relationship between them. In addition, there are various problems to be solved. For this reason, various researchers have studied various methods for producing trans-β-benzoyl acrylate ester, for example, a method using aldol condensation of acetophenone and glyoxylic acid ester (JP-A-57-192622). , Β-benzoylpropionic acid ester is halogenated and then dehydrohalogenated [Journal of the American Chemical Society, 45 , 222 (1923)] and the like have been proposed. However, the former method uses an extremely expensive glyoxylic acid ester, which is difficult to produce, and the latter method involves a multistep reaction including the synthesis of β-benzoylpropionic acid ester, and a low yield. Therefore, it is hard to say that any method is industrially highly practical. Further, as another synthetic method, a method of esterifying trans-β-benzoylacrylic acid with a dialkyl sulfate or an alkyl halide is also conceivable, but use of a toxic reaction reagent or treatment of waste water after the reaction, etc. Since it has various problems, it cannot be said that the method is industrially effective.

(Problems to be Solved by the Invention) Under the circumstances, the present inventors have established a new industrial production method of trans-β-benzoyl acrylate excellent in operability, safety, and economical efficiency. The inventors have eagerly investigated the elucidation of conditions for preferentially producing trans-form esters and conditions for suppressing by-products in the reaction of β-benzoylacrylic acid with alcohol.

(Means and actions for solving the problem) As a result, formula (III) In the esterification reaction by dehydration reaction of β-benzoylacrylic acid and alcohol represented by
(II) (In the formula, R is the same as above), in addition to the target trans-β-benzoylacrylic acid ester, a considerable amount of the general formula (I) (Wherein R is the same as above), a by-product of β-benzoyl-α-alkoxypropionic acid ester and its by-product (I) are dealcoholized in the presence of an acid catalyst to easily react. Finding that it can be converted to the target (II),
The present inventors have completed a simple and efficient method for producing trans-β-benzoyl acrylate.

The present invention can be represented in a schematic diagram as follows.

(In the schematic diagram, R is the same as above, and the compound (III) is a trans form, a cis form or a mixture thereof of β-benzoyl acrylic acid. That is, the present invention is particularly applicable to β-benzoyl acrylic acid (II
Compound (I), which is a by-product in the esterification reaction by dehydration reaction of (I) with alcohol, and useful in the case of dealcoholization in the presence of an acid catalyst to convert to compound (II), high purity trans -Β-benzoyl acrylate (II)
Is an industrially advantageous method.

Trans-β-benzoyl acrylic acid In the case of dehydration reaction from alcohol with alcohol, generally, as shown in the following formula, the target trans-β-benzoyl acrylic acid ester (II) and an alcohol adduct (I) as a by-product are obtained.
A considerable amount of (β-benzoyl-α-alkoxypropionic acid ester) is produced.

(In the formula, R is the same as above.) Conventionally, the by-product of the alcohol adduct (I) has made it difficult to efficiently obtain the highly pure target product (II). However, it became clear that the target compound (II) and the alcohol adduct (I) can be converted into each other, and an equilibrium relationship dominated by the alcohol concentration in the reaction system is established between them, as shown in the following equation. , When alcohol is removed to the outside of the system in the presence of an acid catalyst, the equilibrium tends toward the target product (II), and finally (I) is quantitatively converted to (II), making it extremely easy to obtain the target product of high purity. It is possible to obtain (II).

In this case, (I) can be converted to the target product (II) with an acid catalyst at room temperature or under heating, but equilibrium occurs without removal of the produced alcohol, and transfer to the target product (II) occurs. Will be incomplete. On the other hand, the target product (II) can be efficiently obtained by shifting the equilibrium to the target product (II) by distilling the produced alcohol out of the reaction system under normal pressure or reduced pressure.

Also, cis-β-benzoyl acrylic acid When a similar esterification reaction is carried out using, as shown in the following formula, cis-β-benzoyl acrylate (IV), trans-β-benzoyl acrylate
(II) and alcohol adduct (I) are obtained.

(In the formula, R is the same as above.) In this case, the byproduct alcohol adduct (I) can be converted to the target product (II) as described above, but the compound (IV) produced at the same time is dealcoholated. It was found that under the same reaction conditions as above, the desired trans-β-benzoylacrylic acid ester (II) was easily isomerized by an acid catalyst.

Further, from a practical point of view, it is possible to carry out the reaction in such a manner that the water produced along with the progress of the esterification reaction is removed from the reaction system together with the azeotropic solvent to the outside of the reaction system in a conventional manner, while shifting the equilibrium to the ester formation. preferable. In particular, in the azeotropic dehydration esterification reaction in the vicinity of the stoichiometric alcohol requirement (for example, 1.0 to 1.5 equivalents) with respect to β-benzoylacrylic acid, as shown in the following formula, As the dehydration reaction (esterification) progresses efficiently by removing the generated water, the conversion of alcohol adduct to the target product is promoted due to the decrease of alcohol concentration in the reaction system, and by-product / accumulation of alcohol adduct is suppressed. Then, a complex effect is observed, and the target compound (II) can be efficiently obtained (when cis-β-benzoylacrylic acid is used, the by-product of compound (IV) is produced in the same manner as described above. Isomerization to the desired product (II) occurs).

(In the formula, R is the same as the above.) Therefore, in the present invention, trans-cis or a mixture of trans-cis and β-benzoylacrylic acid is used, and in any case, trans-β having an extremely high purity is used. -Can be derivatized to benzoyl acrylate.

As described above, in the method for producing trans-β-benzoylacrylic acid ester by the esterification reaction of β-benzoylacrylic acid and alcohol, in the presence of an acid catalyst, the alcohol that is a constituent component of the ester is distilled off. It is a feature of the present invention that the by-product or cis-isomer is converted into a target product by the operation.

In the conversion reaction from the compound (I) or the compound (IV) to the target compound (II), the substituent represented by R in the formula is a methyl group, an ethyl group, an n-propyl group, an n-hexyl group. ,
a linear alkyl group such as an n-octyl group; an isobutyl group,
Examples thereof include branched alkyl groups such as isoamyl group; cyclic alkyl groups such as cyclohexyl group; and aralkyl groups such as β-phenylethyl group.

The conversion reaction from the compound (I) or the compound (IV) to the desired product (II) can be carried out without solvent or in an inert solvent such as benzene or toluene. The reaction solvent is benzene,
In addition to using toluene or the like alone, it may be a mixed solvent containing these as main solvents and other solvents to the extent that they do not hinder the progress of the reaction. Examples of the coexisting acid include inorganic mineral acids such as sulfuric acid and hydrochloric acid; organic acids such as paratoluenesulfonic acid; and Lewis acids such as boron trifluoride etherate. The reaction temperature is 20 to 150 ° C., preferably 40 ° C. or higher from the viewpoint of reaction rate and 100 ° C. or lower from the viewpoint of decomposition and coloring of the product. The amount of the acid added is generally 0.02 to 40% based on the reaction mixture in the case of a non-volatile acid such as sulfuric acid or paratoluenesulfonic acid.
(w / v), 10 to 50% for volatile acids such as hydrochloric acid
(w / v). The reaction time is usually several minutes to 5 hours.

The progress of the reaction can be traced by thin layer chromatography. After completion of the reaction, the target trans-
It is possible to obtain β-benzoyl acrylic acid ester (II).

In addition, these conversion reactions are carried out by adding the alcohol adduct (I) or the cis-β-benzoylacrylic acid ester (IV) alone or the mixture of the compounds (I) and (IV) simultaneously to the target compound (II). Can be converted. β-benzoylacrylic acid (III) is reacted with alcohol in the presence of an acid to give compounds (I) and (II), or cis-isomers thereof are used to give compounds (I), (II) and ( IV) is formed in the reaction system, respectively, and then unreacted excess alcohol and alcohol produced in the conversion reaction from the compound (I) to the target compound (II) are removed from the reaction system under normal pressure or reduced pressure. Compound while distilling off
(I) and / or compound (IV) is converted to the target compound (II),
Finally, only the desired product (II) can be isolated.

Further, in the azeotropic dehydration esterification reaction of β-benzoyl acrylic acid and alcohol, the amount of alcohol used is, considering the residual β-benzoyl acrylic acid and the by-product of β-benzoyl-α-alkoxypropionic acid ester. , Β-benzoyl acrylic acid, 1.0-1.5
Around the equivalent is preferable. As the azeotropic solvent, benzene, chloroform, 1,1,1-trichloroethane or the like can be used in the usual manner. The coexisting acid and its amount are as described above. The reaction time is about 1 hour to 15 hours, and after completion of the reaction, the target trans-β-benzoylacrylic acid ester (II) can be obtained by an extraction method or a distillation method. Of course, the β-benzoylacrylic acid used may be a cis isomer, a trans isomer, or a mixture of both isomers.

〔Example〕

The present invention will be described below with reference to examples, but the present invention is not limited thereto.

Example 1 Methyl β-benzoyl-methoxypropionate 268 mg, paratoluenesulfonic acid monohydrate 150 mg
After stirring a mixture of toluene and 5 ml of toluene at 80 ° C. for 1 hour,
The pressure was reduced with an aspirator, and the total amount was concentrated to 1/2. Then, the mixture was stirred as it was at 80 ° C. for 20 minutes and then left to cool.
The reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed with saturated NaHCO ₃ water, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 206 mg of methyl yellow trans-β-benzoyl acrylate. ¹ H NMR (CDCl ₃ , δ) 8.15 to 7.32 (m, phenyl), 7.95 (d, olefin
ic proton), 6.88 (d, olefinic proton), 3.85 (s, ester me
thyl) Example 2 6.45 g ethyl trans-β-benzoyl acrylate, β
-Benzoyl-α-ethoxypropionate ethyl 3.55g
The resulting ethanol was distilled off under reduced pressure to 20 mmHg with an aspirator while stirring the mixture of 100 g of sulfuric acid and 1.80 g of sulfuric acid. After continuing the reaction for 10 minutes, it was cooled.
The same treatment as in Example 1 was carried out to obtain 7.76 g of ethyl trans-β-benzoylacrylate.

Example 3 Ethyl trans-β-benzoyl acrylate 6.79 g, β
-Benzoyl-α-ethoxypropionate ethyl 1.97g
The mixture of 0.12 g of sulfuric acid and sulfuric acid was subjected to distillation under reduced pressure, and trans-
Ethyl β-benzoyl acrylate 7.02 g is 123 to 13
It was distilled at 4 ° C / 3 mmHg.

Example 4 A mixture of 7.75 g of trans-β-benzoylacrylic acid, 25.8 ml of ethanol and 1.63 g of sulfuric acid was stirred at 62 ° C. for 3 hours. Then, the pressure was gradually reduced with an aspirator, ethanol was distilled off over 20 minutes, and finally 2
The mixture was stirred under reduced pressure at 0 mmHg at 62 ° C for 1.5 hours and cooled. Thereafter, the same processing as in the embodiment is performed to perform trans-β.
-8.18 g of ethyl benzoyl acrylate was obtained.

Example 5 A mixture of 5.00 g of trans-β-benzoylacrylic acid, 16.7 ml of n-propyl alcohol and 1.05 g of sulfuric acid was added to 100 parts.
The mixture was stirred at ° C for 1.5 hours. Then, the pressure was gradually reduced with an aspirator, n-propyl alcohol was distilled off over 15 minutes, and finally, the pressure was reduced to 20 mmHg at 100 ° C.
The mixture was stirred for 10 minutes and cooled. Then, the same treatment as in Example 1 was carried out to obtain 5.78 g of n-propyl trans-β-benzoyl acrylate. ¹ H NMR (CDCl ₃ , δ) 8.13 to 7.33 (m, phenyl), 7.94 (d, o)
lefinic proton), 6.88 (d, olefinic proton), 4.20 (t, -O C
H ₂ CH ₂ CH ₃ , methylene), 2.77 (m, -OCH ₂ CH ₂ CH ₃ , methylene),
1.00 (t, -OCH ₂ CH ₂ CH ₃ , methyl) Example 6 A mixture of 200 mg of ethyl cis-β-benzoyl acrylate, 200 mg of boron trifluoride etherate (abt.47%) and 10 ml of toluene at 80 ° C. After stirring for a minute,
The mixture was allowed to cool and then treated in the same manner as in Example 1 to give a yellow oily product of ethyl trans-β-benzoylacrylate 17
5 mg was obtained. ¹ H NMR (CDCl ₃ , δ) 8.10 to 7.35 (m, phenyl), 7.90 (d, o)
lefinic proton), 6.85 (d, olefinic proton), 4.28 (q, -OE
t, methylene), 1.33 (t, -OEt, methyl) Example 7 β-benzoylacrylic acid (cis by ¹ H NMR analysis
/ trans = 1/2) 3.00 g, ethanol 10 ml and sulfuric acid 0.63
The mixture of g was refluxed for 2 hours. Then, the pressure was gradually reduced with an aspirator, ethanol was distilled off over 10 minutes, and finally, the pressure was reduced to 20 mmHg, and the mixture was stirred at 85 ° C. for 40 minutes and cooled. Thereafter, the same treatment as in Example 1 was carried out to obtain ethyl trans-β-benzoylacrylate 2.45.
g was obtained.

Example 8 A mixture of trans-β-benzoylacrylic acid 7.50 g, ethanol 2.36 g, sulfuric acid 0.50 g and chloroform 30 ml was refluxed for 5 hours while azeotropically dehydrating the produced water to remove it from the reaction system. After cooling, the reaction mixture was washed with saturated NaHCO ₃ water and then with water, and the solvent was distilled off to obtain 8.08 g of ethyl trans-β-benzoyl acrylate.

Reference Example A mixture of 7.75 g of trans-β-benzoylacrylic acid, 25.8 ml of ethanol and 1.63 g of sulfuric acid was stirred at 62 ° C. for 3 hours. After cooling, it was diluted with water and extracted with ethyl acetate. Next, the ethyl acetate layer was washed with saturated NaHCO ₃ water, washed with water, and dried over anhydrous magnesium sulfate. 3 pairs of distillation to trans -β- benzoyl acrylate and β- benzoyl -α- ethyl ethoxypropionate solvent 1 ⁽¹ H N
7.86 g of a mixture (according to analysis by MR) was obtained.

(Effect of the Invention) According to the present invention, highly pure trans-β-benzoyl acrylate can be industrially produced advantageously.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location C07B 61/00 300 (72) Inventor Kiyoshi Watanabe 41-5-15 Matsugaoka, Akashi-shi, Hyogo

Claims (12)

[Claims] 1. A general formula (I) (In the formula, R represents an alkyl group or an aralkyl group), the β-benzoyl-α-alkoxypropionic acid ester is dealcoholized in the presence of an acid catalyst to give a compound represented by the general formula (II): (In the formula, R is the same as the above). A method for producing trans-β-benzoyl acrylate, which comprises converting to trans-β-benzoyl acrylate. 2. The production method according to claim 1, wherein the dealcoholization operation is performed by distilling alcohol out of the reaction system. 3. The method according to claim 1 or 2, wherein sulfuric acid is used as the acid. 4. The general formula (I) (In the formula, R represents an alkyl group or an aralkyl group) (R is the same as above) in the coexistence of cis-β-benzoylacrylic acid ester, in the presence of an acid catalyst, dealcoholation is carried out to obtain compounds (I) and (IV) simultaneously with the general formula (II). (R is the same as above). A method for producing trans-β-benzoyl acrylate, which comprises converting to trans-β-benzoyl acrylate. 5. Formula (III) Β-benzoylacrylic acid represented by the following formula is subjected to dehydration esterification reaction with an alcohol represented by the general formula (V) ROH (V) (wherein R represents an alkyl group or an aralkyl group) in the presence of an acid,
Generated general formula (I) The reaction mixture containing β-benzoyl-α-alkoxypropionic acid ester represented by the formula (II) is characterized by dealcoholation in the presence of an acid catalyst. (In the formula, R is the same as the above.) A method for producing a trans-β-benzoyl acrylic acid ester. 6. The formula (III) is trans-β-benzoylacrylic acid, and the β-benzoyl-α-alkoxypropionic acid ester of the compound (I) and the target compound (II) coexist in the reaction mixture. The manufacturing method according to claim 5. 7. The formula (III) comprises cis-β-benzoylacrylic acid, the formula (IV) being included in the reaction mixture. (Wherein R is the same as above) coexisting with the compound (I) and the target compound (II). 8. The production method according to claim 5, 6, or 7, wherein dealcoholization is carried out by distilling alcohol out of the reaction system. 9. Formula (III) Β-benzoylacrylic acid represented by the formula (1) and 1.0 to 1.5 times the equivalent of the alcohol represented by the general formula (V) ROH (V) (wherein R represents an alkyl group or an aralkyl group):
In the presence of an acid, the produced water is reacted by azeotropic dehydration using an azeotropic solvent to give a compound of the general formula (II) (R is the same as above), which promotes the formation of trans-β-benzoyl acrylate.
Method for producing benzoyl acrylate. 10. The production method according to claim 9, wherein sulfuric acid is used as the acid. 11. The method according to claim 9 or 10, wherein the β-benzoylacrylic acid is in the trans form. 12. The method according to claim 9 or 10, wherein the β-benzoylacrylic acid is a mixture of cis isomer and trans isomer.